Glypican 2 as a cancer marker and therapeutic target
Inventors
Maris, John M. • BOSSE, Kristopher R. • Dimitrov, Dimiter • Zhu, Zhongyu • Jelev, Dontcho V.
Assignees
Childrens Hospital of Philadelphia CHOP • US Department of Health and Human Services
Publication Number
US-11814440-B2
Publication Date
2023-11-14
Expiration Date
2036-11-08
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Abstract
The present disclosure is directed to antibodies binding to Glypican 2 and methods of using such antibodies to treat cancers that express or overexpress the Glypican 2 antigen.
Core Innovation
The invention is directed to antibodies that bind to Glypican 2 (GPC2) and methods of using such antibodies to treat cancers that express or overexpress the Glypican 2 antigen. These antibodies include fully human antibodies derived from phage display libraries and are useful in various immunotherapeutic formats including chimeric antigen receptors (CARs), antibody-drug conjugates (ADCs), and bispecific antibodies.
A major problem addressed by the invention is the poor prognosis of children with high-risk neuroblastoma despite intensive chemoradiotherapy and the significant toxicities associated with existing immunotherapies, such as monoclonal antibodies targeting GD2. The invention solves this by identifying GPC2 as a novel cell surface molecule with tumor-specific expression, restricted normal tissue expression, and functional importance in tumor growth and survival, thus providing a promising immunotherapeutic target with potentially fewer toxicities.
The disclosure provides detailed characterization of GPC2 expression, demonstrating its overexpression on the plasma membrane of neuroblastoma cells and other pediatric cancers including medulloblastoma, with restricted normal tissue presence. The invention further includes the development and characterization of antibodies targeting GPC2, methods for generating and engineering such antibodies, including single chain and chimeric antigen receptors, and compositions for treatment including cancer cells expressing GPC2. Combination therapies with other anticancer agents are also described.
Claims Coverage
The claims present nine inventive features focusing on chimeric antigen receptors and engineered cells that involve antibodies or antibody derivatives binding specifically to Glypican 2-positive cancer cells.
Chimeric antigen receptor with Glypican 2-binding monoclonal antibody ectodomain
A chimeric antigen receptor comprising an ectodomain with a single chain antibody variable region derived from an IgG monoclonal antibody that binds cancer cell-associated Glypican 2, wherein the antibody inhibits cancer cell growth and induces cell death, and the ectodomain has a flexible hinge attached at the C-terminus of the antibody variable region; the receptor further includes a transmembrane domain and an endodomain that provides signal transduction upon engagement with Glypican 2.
Engineered cells expressing antibodies or derivatives binding Glypican 2
Isolated engineered cells comprising an antibody or antibody derivative that binds to cancer cell-associated Glypican 2, with the antibody or derivative comprising either the specified complementarity determining region (CDR) amino acid sequences or the full heavy and light chain variable domain amino acid sequences as defined by specific SEQ ID NOs.
Transmembrane and endodomain derivation from the same molecule
The transmembrane and endodomain of the chimeric antigen receptor are derived from the same molecule.
Endodomain with CD3-zeta domain
The endodomain of the chimeric antigen receptor includes a CD3-zeta domain.
Flexible hinge derived from CD8a or immunoglobulin
The flexible hinge attached at the C-terminus of the single chain antibody variable region is from CD8α or an immunoglobulin (Ig).
Endodomain including costimulatory intracellular domain
The endodomain further includes an intracellular domain of a costimulatory protein chosen from CD28, 41BB, OX40, and ICOS.
Chimeric antigen receptor with single chain antibody variable region arranged with flexible hinge
A chimeric antigen receptor having an ectodomain with a single chain antibody variable region that binds Glypican 2, with a flexible hinge at the C-terminus; a transmembrane domain; and an endodomain providing signal transduction after binding. The single chain antibody variable region is formed by fusing the C-terminus of a light chain variable domain to the N-terminus of a heavy chain variable domain via a linker, comprising specified CDR amino acid sequences.
Light and heavy chain variable domains with specified sequences
The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 4, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 2 in the chimeric antigen receptor.
Linker and domain specifics in chimeric antigen receptor
The linker fusing light and heavy chain variable domains can be a peptide, non-peptide, or chemical unit, with a preference for a peptide linker; the transmembrane domain may comprise a CD28 domain; the endodomain may comprise a CD3-zeta domain and further include costimulatory intracellular domains from CD28, 41BB, OX40, or ICOS; and the flexible hinge may be derived from CD8α or an immunoglobulin.
The claims collectively cover chimeric antigen receptors comprising specific Glypican 2-binding antibody sequences with defined structural features such as flexible hinges, transmembrane and endodomains including CD3-zeta and costimulatory domains, as well as engineered cells expressing such antibodies or derivatives, detailing key sequence and domain arrangements for targeted cancer cell recognition and killing.
Stated Advantages
GPC2 antibodies provide tumor-specific targeting with very limited normal tissue expression, potentially reducing on-target off-tumor toxicity compared to existing therapies.
GPC2 targeting may inhibit cancer cell growth and induce cancer cell death, contributing to effective cancer treatment.
The invention provides multiple therapeutic modalities including CAR-T, ADCs, and bispecific antibodies, offering versatility and promising therapeutic activity against GPC2-positive cancers.
Documented Applications
Treatment of cancers expressing or overexpressing Glypican 2, including high-risk neuroblastoma and other pediatric cancers such as medulloblastoma and rhabdoid cancer.
Use of antibodies and derivatives for immunotherapy approaches such as chimeric antigen receptor (CAR) T cell therapy, antibody-drug conjugates (ADCs), and bispecific T-cell engagers (BiTEs) targeting Glypican 2.
Diagnostic methods for detecting Glypican 2 expression in cancer cells via immunodetection techniques including ELISA, western blot, and immunohistochemistry.
Combination therapies incorporating anti-Glypican 2 antibodies with chemotherapy, radiotherapy, immunotherapy, hormonal therapy, or toxin therapy.
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